Systemic lupus erythematosus (SLE) is a chronic, inflammatory autoimmune disease characterized by antinuclear autoantibodies and deposition of immune complexes, leading to organ damage and early death (Alarcon-Segovia et al. (2005) Arthritis Rheum. 52:1138-1147). SLE autoantibodies mediate organ damage by directly binding to host tissues and by forming immune complexes that deposit in vascular tissues and activate immune cells. Organs targeted in SLE include the skin, kidneys, vasculature, joints, various blood elements, and the central nervous system (CNS). The severity of disease, the spectrum of clinical involvement, and the response to therapy vary widely among patients.
The type I interferon (IFN) pathway is activated in human SLE (Blanco et al. (2001) Science 294:1540-1543; Ronnblom and Alm (2001) J. Exp. Med. 194:F59-63; Baechler et al. (2003) Proc. Natl. Acad. Sci. USA 100:2610-2615). Type I IFN is a central mediator of viral immunity (Isaacs and Lindenmann (1957) Proc. R. Soc. B 147:258-273), and many SLE patients strongly overexpress IFN-responsive genes in blood cells (Baechler et al. supra; Bennett et al. (2003) J. Exp. Med. 197:711-723; Kirou et al. (2004) Arthritis Rheum. 50:3958-3967). However, it is not known whether the IFN expression signature is a general biomarker of a dysregulated immune system, or rather reflects primary genetic variation causal to the pathogenesis of human SLE.
IFN regulatory factor 5 (IRF-5) is a member of a family of transcription factors that controls inflammatory and immune responses (Honda et al. (2005) Int. Immunol. 17:1367-1378). IRF-5 has a critical role in the production of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), and IL-6 following toll-like receptor (TLR) signaling as determined by knockout mouse studies (Takaoka et al. (2005) Nature 434:243-249), and is also important for transactivation of type I IFN and IFN-responsive genes (Barnes et al. (2001) J. Biol. Chem. 276:23382-23390; Barnes et al. (2004) J. Biol. Chem. 279:45194-45207).
The clinical heterogeneity of SLE makes it challenging to diagnose and manage this disease. Moreover, current therapy options for SLE are limited, and therapy strategies are highly individualized and tend to include much trial and error. Thus, there is a need for diagnostic technologies for SLE that can identify patients that will likely respond well to particular therapies.